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Isolation of human hepatic microsomes and their inhibition by cimetidine and ranitidine.
Eur J Clin Pharmacol. 1985; 29(2):199-206.EJ

Abstract

Human hepatic microsomes were isolated from wedge biopsies of the liver from 13 patients undergoing abdominal surgery. Ultrasonic homogenisation was used to increase the yield of microsomal monooxygenase activity (7-ethoxycoumarin O-deethylase, NADPH-cytochrome c reductase), resulting in a 30% higher total enzyme activity per g liver than preparation by other techniques. In 4 individual microsomal preparations the influence of cimetidine and ranitidine on Michaelis-Menten kinetics of O-deethylation and of reductase activity were studied. Without the H2-receptor blocking drugs, enzyme kinetics of O-deethylation with a Km of 51.0 +/- 16.4 microM (n = 3) were obtained using Lineweaver-Burke plots. Both, cimetidine and ranitidine inhibited the O-deethylation; cimetidine had a five-fold higher inhibitory affinity (Ki 1.01 and 3.94 mM) to the monooxygenase than ranitidine (Ki 4.96 and 17.70 mM) in the uninduced liver. However, in liver from a patient with induced enzyme activity (Km = 478.0 microM), the Ki of ranitidine was similar to that of cimetidine (Ki ran 3.57 versus Ki cim 2.49 mM). The reductase activity was not inhibited by ranitidine and only marginally so by cimetidine. The results suggest that in human hepatic microsomes oxidative drug metabolism is inhibited by both H2-receptor antagonists. However, the inhibitory potency of the compounds seems to depend on the individual isozyme pattern of the hepatic microsomes. Thus, while cimetidine is an relatively nonspecific enzyme inhibitor, ranitidine might more selectively inhibit induced drug metabolizing enzymes.

Authors

Hoensch HP
No affiliation info available
Hutzel H
No affiliation info available
Kirch W
No affiliation info available
Ohnhaus EE
No affiliation info available

MeSH

7-Alkoxycoumarin O-DealkylaseAdultAgedCimetidineFemaleHumansIn Vitro TechniquesKineticsMaleMicrosomes, LiverMiddle AgedMixed Function OxygenasesNADPH-Ferrihemoprotein ReductaseOxidoreductases, O-DemethylatingOxygenasesRanitidine

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

3935464

Citation

Hoensch, H P., et al. "Isolation of Human Hepatic Microsomes and Their Inhibition By Cimetidine and Ranitidine." European Journal of Clinical Pharmacology, vol. 29, no. 2, 1985, pp. 199-206.
Hoensch HP, Hutzel H, Kirch W, et al. Isolation of human hepatic microsomes and their inhibition by cimetidine and ranitidine. Eur J Clin Pharmacol. 1985;29(2):199-206.
Hoensch, H. P., Hutzel, H., Kirch, W., & Ohnhaus, E. E. (1985). Isolation of human hepatic microsomes and their inhibition by cimetidine and ranitidine. European Journal of Clinical Pharmacology, 29(2), 199-206.
Hoensch HP, et al. Isolation of Human Hepatic Microsomes and Their Inhibition By Cimetidine and Ranitidine. Eur J Clin Pharmacol. 1985;29(2):199-206. PubMed PMID: 3935464.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Isolation of human hepatic microsomes and their inhibition by cimetidine and ranitidine. AU - Hoensch,H P, AU - Hutzel,H, AU - Kirch,W, AU - Ohnhaus,E E, PY - 1985/1/1/pubmed PY - 1985/1/1/medline PY - 1985/1/1/entrez SP - 199 EP - 206 JF - European journal of clinical pharmacology JO - Eur J Clin Pharmacol VL - 29 IS - 2 N2 - Human hepatic microsomes were isolated from wedge biopsies of the liver from 13 patients undergoing abdominal surgery. Ultrasonic homogenisation was used to increase the yield of microsomal monooxygenase activity (7-ethoxycoumarin O-deethylase, NADPH-cytochrome c reductase), resulting in a 30% higher total enzyme activity per g liver than preparation by other techniques. In 4 individual microsomal preparations the influence of cimetidine and ranitidine on Michaelis-Menten kinetics of O-deethylation and of reductase activity were studied. Without the H2-receptor blocking drugs, enzyme kinetics of O-deethylation with a Km of 51.0 +/- 16.4 microM (n = 3) were obtained using Lineweaver-Burke plots. Both, cimetidine and ranitidine inhibited the O-deethylation; cimetidine had a five-fold higher inhibitory affinity (Ki 1.01 and 3.94 mM) to the monooxygenase than ranitidine (Ki 4.96 and 17.70 mM) in the uninduced liver. However, in liver from a patient with induced enzyme activity (Km = 478.0 microM), the Ki of ranitidine was similar to that of cimetidine (Ki ran 3.57 versus Ki cim 2.49 mM). The reductase activity was not inhibited by ranitidine and only marginally so by cimetidine. The results suggest that in human hepatic microsomes oxidative drug metabolism is inhibited by both H2-receptor antagonists. However, the inhibitory potency of the compounds seems to depend on the individual isozyme pattern of the hepatic microsomes. Thus, while cimetidine is an relatively nonspecific enzyme inhibitor, ranitidine might more selectively inhibit induced drug metabolizing enzymes. SN - 0031-6970 UR - https://www.unboundmedicine.com/medline/citation/3935464/Isolation_of_human_hepatic_microsomes_and_their_inhibition_by_cimetidine_and_ranitidine_ DB - PRIME DP - Unbound Medicine ER -